Modeling the 3D structure and conformational dynamics of very large RNAs using coarse-grained molecular simulations

Area of Science:

• Computational biology
• Structural biology
• Biophysics

Background:

• Accurate 3D modeling of large RNA molecules (>1000 nucleotides) is crucial for understanding their function.
• Existing methods struggle with the complexity and size of these biomolecules.
• Simulating RNA dynamics requires robust computational approaches.

Approach:

• Developed a computational method using energy minimization and Brownian dynamics (BD) simulations.
• Incorporated a 4th spatial dimension to disentangle helical elements.
• Included hydrodynamic interactions (HI) to model diffusive and conformational dynamics.

Key Points:

• Validated the method by accurately reproducing experimental hydrodynamic radii (Rh) for small RNAs.
• Demonstrated good agreement between simulated and experimental Rh for large RNAs (85-3569 nucleotides).
• Showed that 100 µs timescale conformational dynamics sampling is computationally feasible for large RNAs.

Conclusions:

• The developed BD-HI simulation protocol provides a reliable tool for modeling large RNA structures and dynamics.
• This method is particularly effective for RNAs lacking persistent tertiary contacts.
• Enables in-silico exploration of large RNA conformational landscapes.